2-mercaptobenzimidazole derivatives possessing pharmacological activity

ABSTRACT

2-mercaptobenzimidazole derivatives of the general formula                    
     wherein: N=0,2,3; R-hydrogen atom, aralkyls; R1-lower alkyls, alkenyls, dialkylamino, a saturated amine monocyclic residue which may contain an additional heteroatom; R 2  and R 3  are equal or different and stand for hydrogen atoms, lower alkyls, alkoxy in various positions, and their pharmaceutically acceptable salts, according to the results of pharmacological research study exhibit a pronounced anxiolytic, sedative, antiischemia and antiarrhythmia effect and have certain advantages over popular clinic preparations. These can find a wide variety of application for treatment of patients suffering from various mental derangements and heart ischemia.

This application is a 371 of PCT/RU95/00085 filed May 17, 1995.

THE FIELD OF TECHNIQUES

The invention relates to new S- and N,S-substituted2-mercaptobenzimidazoles which can be useful as the pharmaceuticalagents and pharmacological compositions including these compounds. Theapplied compounds are the pharmacologically active drugs which possesspsychotropic and cardiovascular actions depending on their structure.They can be used in medicine for treatment of different neuropsychiatricdisturbances and ischemic heart disease.

THE PRECEDING LEVEL OF TECHNIQUES

The preparation of numerous substituted 2-mercaptobenzimidazolespossessing different biological activities is known in the literature.The first information about the activity of this series appeared in 1958when Knobloch W. et al. [Arch.Pharmaz., 1958, 291, p.113-118] andNakajima S. et al. [Yakugaku Zasshi, 1958, 78, p.1378-1388] describedthe synthesis of different 2-alkyl-, alkenyl-, aralkyl-,dialkylaminoalkylbenzimidazoles having anti-fungal activity. In thefollowing numerous papers [Nakajima S. et al., Jap.Pat., 10978 ('61),(1961); Hideg K. et al., Brit.Pat., 1234058, (1971); Xin Tao et al.,Zhongguo Yiyao Gongye Zazhi, 1990, 21 (8), p.347-350; Johnson C. A. etal., Med.Chem.Rec., 1992, 2 (4), p.247-255; Onkol et al.,J.Fac.Pharm.Gazz.Univ., 1992, 9 (1), p.47-57; etc.] there were discribed2-mercaptobenzimidazoles with different substitutions in S-, N- andbenzol ring possessing bacteriostatic, insecticidal and anthelminthicactivities.

There was reported about Anti-inflammatory, antipyretic andantidepressant activities of differentS-substituted-2-mercaptobenzimidazoles were reported in French SpecialMedicament Patent. The data about anti-inflammatory and analgeticactivities of the 2-mercaptobenzimidazole derivatives are described inpapers of Seki et al. [Yakugaku Zasshi, 1962, 82, p.1620-1624], HasegawaH. et al. [Jap.Pat., 7441198 (1974)], Aka T. et al. [Jap.Pat., 9888('64) (1964)], Lafon V. et al. [Ger.Offen 2246429 (1978)], Rao V.,Madhusudan et al. [Indian Drugs, 1987, 24 (12), p.545-548], Lazer E. S.et al. [J.Med.Chem., 1987, 30, p.726-729].

The synthesis of 2-dialkylaminoalkylbenzimidazoles substituted in N-atomwith anti-histaminic and anti-allergic properties was described by GianiR. et al. [Eur.Pat.Appl. EP334818 (1989)] and Dini S. et al. [AgentsActions, 1990, 30, p.174-177].

There have been patented many differentS-substituted-2-mercaptobenzimidazoles with anti-ulcerous activity[Machinami T. et al., Eur.Pat.Appl. EP 452076 (1991); Lang H. J. et al.,Eur.Pat.Appl. EP 213474 (1987); Adelstein G. W. et al., Eur.Pat.Appl. EP204215 (1986); Okitsu M., Jpn. Kokai Tokkyo Koho JP 62230773 (1987);Hirai K. et al., Jpn. Kokai Tokkyo Koho JP 62331158 (1987); Okabe S. etal., Jpn. Kokai Tokkyo Koho JP 03227927 (1991); Riedel R. et al., PCTInt.Appl. WO 87/01114 (1986); Klemm K. et al., PCT Int.Appl. WO 9204898(1992) etc.]. Some of them—omeprazol, lansoprazol are widely used inclinical practice.

Synthesis of N-substituted-2-alkylthiobenzimidazoles possessing theproperties of antagonists of angiotensin II and inhibitors ofdopamine-β-hydroxylase was reported in the patents of Hauel et al.[Eur.Pat.Appl. EP 502314 (1992)] and Smithkline Beckman Corp. [Jpn.Kokai Tokkyo Koho JP 61161267 (1986)].

There are known some papers describing the synthesis of some2-mercaptobenzimidazole derivatives with cardiotonic, vasodilative,anti-hypertensive, anti-atherosclerotic and anti-agglutinate properties[Osawa Y. et al., Yakugaku Zasshi, 1968, 88 (6), p.747-754; Brukshtus A.B. et al., Khimiko-Farmatcevt.Zhurnal, 1992, N 11-12, p.50-53; 1994, N6, p.24-26; Bru-Magniez N. et al., Eur.Pat.Appl. EP 385850 (1990);Harsanyi K. et al., UK Pat.Appl. GB 217319A (1986)]. There were revealedsome compounds with anti-ischemic, anti-arrhythmic and anti-hypoxantactivities among synthesized 2-dialkylamino-alkylthiobenzimidazoles[Patent of Russia, 2027709 (1991)].

Some substituted 2-mercaptobenzimidaziles with butyrophenon in the 1stposition are characterised by psychotropic properties including thetranquilising and neuroleptic types of activity [Sato Makoto et al.,Japan Kokai 7584578 (1975); 76136674 (1976); 76146473 (1976)].

The bemityl-2-ethylbenzimidazole hydrobromide is used in clinicalpractice as the psychostimulator and antihypoxant for the treatment ofasthenic and asthenic-depressant disturbances according to the data ofBobkov Yu. G. et al. [Author Certificate of USSR 1251374 (1986)] andNeznamov G. G. et al. [Physiol.Active Drugs, 1993, 25, p.45-49].According to Losinskyi M. O. et al. [Author Certificate of USSR 1259652(1986)] the bemityl's analogue-5-ethoxy-2-ethylthiobenzimidazoleproduces the stress-protective and antihypoxant activities. Plotnikov E.M. et al. [Physiol.Active Drugs, 1993, 25, p.30-34] and Ratnikov L. I.et al. [Physiol.Active Drugs, 1993, 25, p.27-29] have shown that thesecompounds may be used for the treatment of acute cerebrovasculardisturbances and acute respiratory viral infections.

DISCLOSURE OF THE INVENTION

The compounds of the present invention are derivatives of2-mercaptobenzimidazole general formula

where in n=0,2,3; R-hydrogen atom, aralkyls; R¹-lower alkyls, alkenyls,dialkylamino, monocyclic saturated amino group, which can containadditional heteroatom; R² and R³-identical or different and representhydrogen atoms. lower alkyls, alkoxy in various positions. Thesecompounds have tranquilising activity with selective component,sedative, anti-ischaemic and anti-arrithmic activity and can be used inmedicine.

The applied compounds and their pharmaceutically acceptable salts weresynthesized by standard method of alkylation 2-mercaptobenzimidazoles bycorresponding agents in ethanol-water medium in the presence of base(sodium hydroxide) with following treatment of obtaining oily orcrystalline bases in the solution of absolute ethanol or ether withethanolic or etherial solution of gaseous hydrogen chloride:

wherein n, R, R¹, R², R³ have foregoing sense; X-atom of chlorine orbromine; m=1,2,3.

Variant of the Realization of the Invention

The reaction processes were controlled by using TLC—Silufol UV 254 orDC-Alufolien Aluminiumoxid 60 F 254 (Merk), spots were detected by uvabsorbance or iodine vapor. Melting points were determined in the openedcappilaries and were not corrected. NMR spectra were recorded withAC-250 Bruker using CDCl₃ or D₂O as solvent and tetramethylsilane asinternal reference.

The invention was illustrated by the following examples.

Example 1. 2-Ethylthio-5,6-dimethylbenzimidazole (I). 0,65 g (6 mmol)Ethylbromide was added to a solution 0,89 g (0,005 mol)2-mercapto-5,6-dimethylbenzimidazole and 0,24 g (0,006 mol) sodiumhydroxide in 1 ml of water and 10 ml of ethanol. The reaction mixturewas refluxed for 1.5 hr before disappearing starting thione (control byusing TLS), cooled and added water. The precipitated product wasfiltered off, washed with water and dried under atmospheric conditions.The yield was 0,91 g (88%) of compound I, m.p. 123-124° C. (fromwater-ethanol).¹H NMR (CDCl₃), δ: 1.37 (3H, t, CH₂ CH ₃); 2,32 (6H, s,2CH₃); 3,27 (2H, q, CH ₂CH₃); 7,31 (2H, s, ArH).

Calcd for C₁₁H₁₄N₂S: C 64,0; H 6,8; N 13,61 S 15,5; Found: C 63,9; H6,8; N 13,4; S 15,5.

Example 2. 2-Propylthio-5,6-dimethylbenzimidazole (II) was prepared bythe same procedure for I from 0,89 g (0,005 mol)2-mercapto-5,6-dimethyl-benzimidazole, 0,8 g (0,006 mol) propylbromidein the presence 0,24 g (0,006 mol) sodium hydroxide in a yield of 0,72 g(60%), m.p. 122-123° C. (from mixture ethylacetate with hexane).

Calcd for C₁₂H₁₆N₂S. C 64,2; H 7,2; N 12,5; S 14,3; Found: C 64,7; H7,2; N 12,6; S 14,4.

Example 3. 2-Allylthio-5,6-dimethylbenzimidazole (III) was prepared asdescribed above for I from 2,67 g (0,015 mol)2-mercapto-5,6-dimethyl-benzimidazole, 2,1 g (0,017 mol) allylbromide inthe presence 0,7 g (0,017 mol) sodium hydroxide, yield 2,5 g (76%), m.p.119-120° C. (from mixture ethylacetate with hexane). ¹H NMR (CDCl₃), δ:2,33 (6H, s, 2CH₃); 3,89 (2H, d, CH₂S); 5,10 (H_(B), d,CH_(C)═CH_(A)H_(B)); 5,25 (H_(A),d, CH_(C)═CH_(A)CH_(B)); 7,30 (2H,broad s, ArH); 10,11 (1H, broad s, NH).

Calcd for C₁₂H₁₄N₂S: N 12,8; S 14,7; Found: N 12,7; S 14,7.

Hydrochloride of base III, yield 93%, m.p. 204-205° C. (with decomp.;from abs. ethanol).

Cacld for C₁₂H₁₄N₂S*HCl. C 56,6; H 5,9; Cl 13,9; N 11,0; S 12,6.

Example 4. 2-Allylthio-5-ethoxybenzimidazole (IV) and its hydrochoride.To a solution 1,95 g (0,010 mol) 2-mercapto-5-ethoxybenzimidazole and0,44 g (0,011 mol) sodium hydroxide in 2 ml of water and 20 ml ofethanol was added 1,32 g (0,011 mol) allylbromide. The reaction mixturewas refluxed for 3 hr, cooled and diluted with water, the forming oilwas extracted with ether, dried over anhedrous magnesium sulfate,filtered and the solvent was removed. The compound IV was obtained as anoil, which was disolved in abs. ether and treated with etherial solutionof HCl. The precipitate was filtered, washed with abs. ether and driedunder atmospheric condition. The yield was 2 g (74%) of hydrochloride ofbase IV, m.p. 147-149° C. (decomp.; from abs. ethanol with ether). ¹HNMR (D₂O), δ: 1,54 (3H, t, CH₂ CH ₃); 4,05 (2H, d, CH₂S); 4,18 (2H, q,CH ₂CH₃); 5,34 (H_(B), d, CH_(C)═CH_(A)H_(B)); 5,42 (H_(A), d,CH_(C)═CH_(A)CH_(B)); 6,11 (H_(C), m, CH_(C)═CH_(A)H_(B)); 7,07 (1H,broad s, 4-H); 7,09 (1H, dd, 6-H); 7,53 (1H, d, 7-H).

Calcd for C₁₂H₁₄N₂OS*HCl: C 53,2; H 5,6; Cl 13,1; N 10,3; S 11,8. Found:C 53,4; H 5,6; Cl 13,11 N 10,3; S 11,9.

Example 5.2-[2-(Dimethylamino)ethylthio]-5-methoxybenzimidazole and itshydrochloride were obtained as described above. The reaction of 3,6 g(0,020 mol) 2-mercapto-5-methoxybenzimidazole, 3,17 g (0,022 mol)2-(dimethyl-amino)-ethylchloride hydrochloride in the presence 1,8 g(0,044 mol) sodium hydroxide gave V as an oil, from which itsdihydrochloride was prepared in a yield of 4,5 g (69%), m.p. 252-254° C.(decomp., from ethanol with charcoal). ¹H NMR (D₂O), δ: 3,07 (6H, s,(CH₃)₂N); 3,67 (2H, m, CH₂S); 3,82 (2H, m, CH₂N); 3,96 (3H, s, CH₃O);7,16 (1H, broad s, 4-H), 7,17 (1H, d, J_(6,7)9,5,6-H); 7,57 (1H,J_(7,6)9,5, 7-H).

Calcd for C₁₂H₁₇N₃OS*2HCl: C 44,4; H 5.9; Cl 21,9; N 13,0; S 9,9. Found:C 44,3; H 5,8; Cl 21,7; N 12,5; S 9,7.

Example 6. 2-2-[(Diethylamino)ethylthio]-5-ethoxybenzo-imidazole (VI)and its dihydrochloride were obtained as described above. The reactionof 3,6 g (0,020 mol) 2-mercapto-5-ethoxybenzimidazole, 4,4 g (0,022 mol)2-(diethyl-amino)ethyl-chloride hydrochloride gave an oily base VI, fromwhich its hydrochloride was prepared in a yield of 4,4 g (62%), m.p.209-210° C. (with decomp., from ethanol with charcoal). ¹H NMR (D₂O), δ:1,37 (6H, t, 2 CH₂ CH ₃); 3,40 (4H, q, 2 CH ₂CH₃); 3,63 (2H, m, CH₂S);3,79 (2H, m CH₂N); 3,93 (3H, s, CH₃O); 7,12 (1H, broad s, 4-H); 7,13(1H, dd, J_(4,6)1,5, J_(6,7)9,5, 6-H); 7,56 (1H, d, J_(7,6)9,5, 7-H).

Calcd for C₁₄H₂₁N₃OS*2HCl: C 47,7; H 6,6; Cl 20,1; N 11,9; S 9,1; FoundC 47,7; H 6,4; Cl 20,3; N 12,2; S 8,5.

Example 7.2-[2-(Piperidino)ethylthio]-5-methoxybenzimidazole (VII) andits dihydrochloride were prepared as described above. The reaction of2,7 g (0,015 mol) 2-mercapto-5-methoxybenzimidazole and 3,03 g (0,016mol) 2-(piperidino)ethylchloride hydrochloride in the presence of 1,4 g(0,034 mol) sodium hydroxide gave an oily base VII, from which itshydrochloride was obtained in a yield of 3,15 g (58%), m.p. 210-212° C.(with decomp., from mixture abs. ethanol with ether).

Calcd for C₁₅H₂₁N₃OS*2HCl: C 49,5; H 6,4; Cl 19,5; N 11,5; S 8,8; Found:C 49,6; H 6,2; Cl 19,3; N 11,3; S 9,0.

Example 8. 2-[2-Dimethylamino)ethylthio]-5-ethoxybenzo-imidazole (VIII)and its dihydrochloride were synthesized as described above. Thereaction of 1,94 g (0,010 mol) 2-mercapto-5-ethoxybenzimidazole and 1,72g (0,012 mol) 2-(dimethylamino)ethylchloride hydrochloride in thepresence of 0,9 g (0,022 mol) sodium hydroxide gave 1,9 g (72%) compoundVIII, m.p. 95-97° C. (from ethanol with water). ¹H NMR (CDCl₃), δ: 1,40(3H, t, CH ₃CH₂O); 2,40 (6H, s, (CH₃)₂N); 2,84 (2H, t, CH₂S); 3,17 (2H,t, CH₂N); 4,05 (2H, q, CH₃ CH ₂O); 6,82 (1H, dd, J_(4,6)2,38,J_(6,7)8,76, 6-H); 6,94 (1H, broad s, 4-H); 7,36 (1H, d, J_(7,6)8 76,7-H). Dihydrochloride of base VIII, yield 77%, m.p. 223-227° C. (withdecomp., from mixture abs. ethanol with ethylacetate).

Calcd for C₁₃H₁₉N₃OS*2HCl: C 46,2; H 6,3; Cl 21,0; N 12,4; S 9,5; Found:C 46,4; H 6,2; Cl 20,7; N 12,2; S 9,6.

Example 9. 2-[2-(Diethylamino)ethylthio]-5-ethoxybenz-imidazole (IX) andits dihydrochloride were synthesized as described above. The reaction of3,9 g (0,020 mol) 2-mercapto-5-ethoxybenzimidazole and 4,4 g (0,022 mol)2-(diethylamino)-ethylchloride hydrochloride in the presence of 1,8 g(0,044 mol) sodium hydroxide gave an oily base IX, from. which itsdihydrochloride was obtained in a yield of 4,4 g (57%), m.p. 169-171° C.(with decomp., from ethanol with ether). ¹H NMR (D₂O), δ: 1,42 (6H, t,(CH ₃CH₂)₂N); 1,53 (3H, t, CH₃CH₂O); 3,44 (4H, q, (CH₃ CH ₂)₂N); 3,68(2H, t, CH₂S); 3,82 (2H, t, CH₂N); 4,19 (2H, q, CH₃ CH ₂O); 7,19 (1H,broad s, 4-H); 7,21 (1H, unresolv.d, 6-H); 7,59 (1H, d, J_(7,6)9,75,7-H).

Calcd for C₁₅H₂₃N₃OS*2HCl*H₂O: C 46,9; H 7,1; Cl 18,5; N 10,9; S 8,3;Found: C 46,9; H 6,8; Cl 18,6; N 10,6; S 8,0.

Example 10. 2-[2-(Pyrrolidino)ethylthio]-5-ethoxybenzimidazole (X) andits dihydrochloride were sythesized as described above. The reaction of1,94 g (0,010 mol) 2-mercapto-5-ethoxybenzimnidazole and 2,04 g (0,012mol) 2-(pyrrolidino)ethylchloride hydrochloride in the presence of 0,9 g(0,022 mol) sodium hydroxide gave X as an oil, which was converted intoits dihydrochloride in a yield of 2,7 g (72%), m.p. 127-130° C. (withdecomp., from abs. ethanol with ether).

Calcd for C₁₅H₂₁N₃OS*2HCl*0,5H₂O: C 48,3; H 6,5; Cl 19,0; N 11,3; S 8,6;Found: C 48,6; H 6,8; Cl 19,0, N 10,9; S 8,7.

Example 11. 2-[2-Piperidino)ethylthio]-5-ethoxybenzimidazole (XI) andits dihydrochloride were synthesized as described above. The reaction of1,94 g (0,010 mol) 2-mercapto-5-ethoxybenzimidazole and 2,21 g (0,012mol) 2-(piperidino)ethylchloride hydrochloride in the presence of 0,9 g(0,022 mol) sodium hydroxide gave base XI as an oil, from which itshydrochloride was prepared in a yield of 2,1 g (57%), m.p. 187-190°(with decomp., from mixture abs.ethanol with ethylacetate).

Calcd for C₁₆H₂₃N₃OS*2HCl*0,5H₂O: C 49,6; H 6,8; Cl 18,3; N 10,9; S 6,2.Found: C 49,6; H 6,7; Cl 18,5; N 10,8; S 6,0.

Example 12. 2-[2-(Morpholino)ethylthio]-5-ethoxybenzimidazole (XII) andits dihydrochloride were synthesized as described above. The compoundXII was obtained as an oil from 2,9 g (0,015 mol)2-mercapto-5-ethoxybenzimidazole and 3,45 g (0,018 mol)2-(morpholino)ethylchloride hydrochloride in the presence of 1,35 g(0,033 mol) sodium hydroxide. The oil was disolved in ethylacetate,extracted by 10% solution hydrochloric acid, the layers were separated,the aqueous phase was refluxed with charcoal, was filtered and was madealkaline with the solution of sodium hydroxide. The obtained oil wasextracted with ethylacetate, washed with water, dried over anhydrousmagnesium sulfate, the solvent was evaporated. The compound XII wasobtained in 87% yield (4 g) as an oil. ¹N NMR (CDCl₃), δ: 1,48 (3H, t,CH₂ CH ₃); 2,59 (4H, m, CH₂NCH₂ of morpholine); 3,24 (2H, m, CH₂N); 3 79(4H, m CH₂OCH₂ of morpholine); 4,02 (2H, q, CH ₂CH₃); 6,82 (1H, dd,J_(4,6) 2,38, J_(6,7)8,77, 6-H); 7,00 (1H, broad s, 4-H); 7,41 (1H, d,J_(7,6)8,77, 7-H).

Calcd for C₁₅H₂₁N₃O₂S. C 58,6; H 6,9; N 13,7; S 10,4; Found: C 58,6; H6,8; N 13,9; S 10,1.

Dihydrochloride of compound XII, yield 91%, m.p. 191-192° C. (withdecomp., from ethanol with charcoal). ¹H NMR (D₂O), δ: 1,54 (3H, t, OCH₂CH ₃); 3,58 (4H, ?m, CH₂NCH₂ of morpholine); 3,74 (2H, m, CH₂S); 3,86(2H, m, CH₂N); 4,12 (4H, unresolv. m, CH₂OCH₂ of morpholine); 4,25 (2H,q, OCH ₂CH₃); 7,21 (1H, d, J_(6,7)8,76, 6-H); 7,22 (1H, s, 4-H); 7,41(1H, d, J_(7,6)8,76 7-H).

Calcd for C₁₅H₂₁N₃O₂S*2HCl. C 47,4; H 6,1; Cl 18,6; N 11,0; S 8,4;Found: C 47,3; H 6,1; Cl 18,6; N 11,0; S 8,4.

Example 13. 2-[2-(Pyrrolidino)ethylthio]-5,6-dimethylbenzimidazole(XIII) and its dihydrochloride were synthesized as described above. Thecompound XIII was obtained from 2,67 g (0,015 mol)2-mercapto-5,6-dimethylbenzimidazole and 2,9 g (0,017 mol)2-(pyrrolidino)ethylchloridehydrochloride in the presence 1,35 g (0,034mol) sodium hydroxide in 90% yield (4,0 g, counting on monohydrate),m.p. 115-116° C. (with decomp., from ethanol with water). ¹H NMR(CDCl₃), δ: 1,97 (4H, m, β-H of pyrrolidine); 2,34 (6H, s, 2CH₃); 2,72(4H, m, -H of pyrrolidine); 3,02 (2H, m, CH₂S); 3,19 (2H, m, CH₂N); 7,18(2H, broad s, ArH).

Calcd for C₁₅H₂₁N₃S*H₂O: C 61,4; H 7,8; N 14,3; S 10,9; Found: C 61,4; H7,8; N 14,5; S 10,9.

Dihydrochloride of XIII, quantitative yield, decomp.p. 240° C. (fromabs.ethanol with ethylacetate).

Calcd for C₁₅H₂₁N₃S*2HCl: C 51,7; H 6,7; Cl 20,4; N 12,1; Found: C 51,7;H 6,5; Cl 20,4; N 12,1.

Example 14.2-[2-(Piperidino)ethylthio]-5,6-dimethylbenzimidazole (XIV)and its dihydrochloride were synthesized as described above. Thereaction of 2,67 g (0,015 mol) 2-mercapto-5,6-dimethylbenzimidazole with3,13 g (0,017 mol) 2-(piperidino)ethylchloride hydrochloride in thepresence of 1,36 g (0,034 mol) sodium hydroxide gave in 93% yield(counting on monohydrate) 4,3 g of compound XIV, m.p. 117-119° C. (withdecomp., from ethanol with water). ¹H NMR (CDCl₃), δ:1,65 (2H, broad m,γ-H of piperidine); 1,82 (4H, m, β-H of piperidine); 2,34 (6H, s, 2CH₃);2,63 (4H, broad m, α-H of piperidine); 2,90 (2H, m, CH₂S); 3,10 (2H, m,CH₂N); 7,26 (2H, broad s, ArH).

Calcd for C₁₆H₂₃N₃S*H₂O: C 62,5; H 8,2; N 13,7; S 10,4. Found: C 62,7; H8,0; N 13,6; S 10,5.

Dihydrochloride of XIV, yield 90%, p.decomp. 242-245° C. (from mixtureabs. ethanol with ethylacetate).

Calcd for C₁₆H₂₃N₃S*2HCl*0,25H₂O: C 52,4; H 7,0; Cl 19,3; N 11,4; S 8,7.

Example 15.2-[2-(Morpholino)ethylthio]-5,6-dimethylbenzimidazole(XV) andits dihydrochloride were synthesized as described above. The reaction of2,67 g (0,015 mmol) 2-mercapto-5,6-dimethylbenzimidazole with 2,8 g(0,015 mol) 2-(morpholino)ethylchloride hydrochloride in the presence of1,2 g (0,030 mol) sodium hydroxide gave in 69% yield of 2,95 g ofcompound XV, m.p. 147-148° C. (from ethylacetate with hexane). ¹H NMR(CDCl₃), δ: 2,32 (6H, s, 2CH₃); 3,62 (4H, m, CH₂NCH₂ of morpholine);2,86 (2H, m CH₂S); 3,21 (2H, m CH₂N); 3,83 (4H,m, CH₂OCH₂ ofmorpholine); 7,27 (2H, broad s, ArH).

Calcd for C₁₅H₂₁N₃OS: C 58,2; H 7,5; N 14,5; S 11,0. Found: C 58,0; H7,3; N 14,5; S 11,1.

Dihydrochloride of XV, yield 96%, m.p. 250-252° C. (with decomp., fromabs. ethanol).

Calcd for C₁₅H₂₁N₃OS*2HCl: C 49,4; H 6,4; Cl 19,5; N 11,5; S 8,8. Found:C 49,4; H 6,5; Cl 19,8; N 11,6; S 8,5.

Example 16.2-[3-(Dimethylamino)propylthio]-5,6-dimethylbenzimidazole(XVI) and its dihydrochloride were synthesized as described above. Thecompound XVI was obtained from 2,67 g (0,015 mol)2-mercapto-5,6-dimethylbenzimidazole and 2,78 g (0,019 mol)3-(dimethyl)propylchloride hydrochloride in the presence 1,32 g (0,033mol) sodium hydroxide in 73% yield (3,1 g), m.p. 95-98° C. (from ethanolwith water). ¹H NMR (CDCl₃), δ: 1,91 (2H, m, CH₂ CH ₂CH₂); 2,32 (6H, s,2CH₃); 2,34 (6H, s, (CH₃)₂N); 2,53 (2H, t, CH₂S); 3,18 (2H,t, CH₂N);7,17 (2H, broad s, ArH).

Calcd for C₁₄H₂₁N₃S*H₂O: C 59,8; H 8,2; N 14,9. Found: C 59,8; H 8,2; N14,7.

Dihydrochloride of XVI, yield 84%, m.p. 206-208° C. (with decomp., frommixture abs. ethanol with hexane).

Calcd for C₁₄H₂₁N₃S*HCl: C 50,0; H 6,9; Cl 21,1; N 12,5; S 9,5.

Example 17.2-[3-(4-Methylpyperazino)propylthio]-5,6-dimethylbenzimidazole (XVII)and its trihydrochloride were synthesized as described above. Thereaction of 2,8 g (0,010 mol) 2-mercapto-5,6-dimethylbenzimidazole and3,74 g (0,015 mol) 3-(4-methylpyperazino)propylchloride dihydrochloridein the presence 1,32 g (0,033 mol) sodium hydroxide gave in 79% yield(2,5 g) compound XVII, m.p. 116-118° C. (with decomp., from chloroformwith hexane). ¹H NMR (CDCl₃), δ: 1,95 (2H, m, CH₂ CH ₂CH₂); 2,31 (6H, s,2CH₃); 2,35 (3H, s, CH₂N); 2,54 (10H, broad m, 8H of pyperazine, 2H, t,CH₂S); 3,22 (2H, t, CH₂N); 7,50 (2H, broad s, ArH). Trihydrochloride ofXVII, yield 78%, m.p. 228-231° C. (with decomp., from ethanol).

Calcd for C₁₇H₂₆N₄S*3HCl*H₂O: C 45,9; H 7,0; Cl 23.9; N 12,6; S 7,2.Found: C 45,8; H 6,9; Cl 23,8; N 12,9; S 7,4.

Example 18. 1-Benzyl-2-[2-(dimethylamino)ethylthuo]benzimidazole (XVIII)and its dihydrochloride. To the suspension of 4,8 g (0,020 mol)1-benzyl-2-mercaptobenzimidazole in the 10 ml water and 40 ml ethanolwas added 1,8 g (0,044 mol) sodium hydroxide and was heated at 70°before dissolving of the precipitate. To the solution at 70° was added3,16 g (0,022 mol) 2-(dimethylamino)ethylchloride hydrochloride. Thereaction mixture was stirred for 3 hr, cooled, NaCl was filtered off andwashed with ethanol. The solvent removed and was obtained the compoundXVIII as an oil, which was dissolved in abs. ethanol, the solution wastreated of ethanol with gaseous HCl. The precipitate was filtered ,washed with abs. ether. The yield of dihydrochloride of XVIII was 5 g(62%), m.p. 190-191° C. (from ethanol). ¹H NMR (D₂O), δ: 3,15 (6H, s,(CH₃)₂N); 3,66 (2H, m, CH₂S); 3,94 (2H, m, CH₂N); 5,78 (2H, s, CH₂Ar);7,43-8,0 (9H, m, ArH).

Calcd for C₁₈H₂₁N₃S*2HCl*0,5H₂O: C 54,9; H 6,1; Cl 18,0; N 10,7; S 8,9.Found: C 55,0; H 5,9; Cl 17,8; N 10,8; S 8,8.

Example 19. 1-Benzyl-2-[2-(diethylarnino)ethylthio]benzimidazole (XIX)and its dihydrochloride were synthesized as described above. Thereaction of 4,8 g (0,020 mol) 1-benzyl-2-mercaptobenzimidazole and 3,8 g(0,022 mol) 2-(diethylamino)ethylchloride hydrochloride in the presence1,8 g (0,044 mol) sodium hydroxide gave the compound XIX as an oil,which was converted into its dihydrochloride in 83%o yield, m.p.136-137° C. (from abs. ethanol with ether). ¹H NMR (D₂O), δ: 1,37 (6H,t, (CH ₃CH₂)₂N); 3,34 (4H, q, (CH₃ CH ₂)₂N); 3,47 (2H, m, CH₂S); 3,79(2H, m CH₂N); 5,75 (2H, s, CH₂Ar); 7,3-7,99 (9H), m, ArH).

Calcd for C₂₀H₂₅N₃S*2HCl*0,5H₂O: C 57,0; H 6,7; Cl 16,8; N 10,0; S 7,6.Found:. C 56,5; H 6,7; Cl 16,8; N 10,0; S 7,9.

Example 20.1-(β-Phenylethyl)-2-[2-(dimethylamino)ethylthio]-benzimidazole (XX) andits dihydrochloride were synthesized as described above. The reaction of2,54 g (0,010 mol) 1-(β-phenylethyl)-2-mercaptobenzimidazole and 1,73 g(0,012 mol) 2-(dimethylamino)ethylchloride hydrochloride in the presenceof 1 g (0,025 mol) sodium hydroxide gave compound XX, which was turnedinto its dihydrochloride in 47% yield (1,7 g), m.p. 160-161° C. (fromabs. ethanol with ether). ¹H NMR (D₂O), δ: 2,99 (6H, s, (CH₃)₂N); 3,27(2H, t, CH₂Ar); 3,38 (2H, t, CH₂S); 3,55 (2H, t, CH₂N); 4,77 (2H, t,CH₂N_(cycl.)); 6,65-7,60 (9H, m, ArH).

Calcd for C₁₉H₂₃N₃S*2HCl*0,5H₂O: C 56,0; H 6,4; Cl 17,4; N 10,3; S 7,9.Found: C 56,3; H 6,0; Cl 17,6; N 10,3; S 7,9.

The solution of dihydrochloride in water was made neutral with solutionof sodium bicarbonate, was extracted with ether, dried over anhydrousmagnesium sulfate, filtered, the solvent was removed, the compound XXwas obtained, m.p. 38-39° C. (petroleum ether). ¹H NMR (CDCl₃), δ: 2,33(6H, s, (CH₃)₂N); 2,72 (2H, t, CH₂S); 3,06 (2H, m, CH₂Ar); 3,53 (2H, t,CH₂N); 4,31 (2H, s, CH₂N_(cycl.)); 7,10-7,70 (9H, m, ArH).

Calcd for C₁₉H₂₃N₃S: C 70,1; H 7,1; N 12,9; S 9,9. Found: C 70,1; H 7,1;N 12,9; S 9,8.

Example 21. 1-(β-Phenylethyl)-2-[2-(diethylamino)ethylthio]benzimidazole(XXI) and its dihydrochloride were synthesized as described above. Thereaction of 2,54 g (0,010 mol) 1-(β-phenylethyl)-2-mercaptobenzimidazoleand 2,1 g (0,012 mol) 2-(diethylamino)ethylchloride hydrochloride in thepresence 1 g (0,025 mol) sodium hydroxide gave in 62% (2,2 g) compoundXXI, m.p. 54-55° C. (from petroleum ether). ¹H NMR (CDCl₃), δ: 1,05 (6H,t, (CH ₃CH₂)₂N); 2,61 (4H, q, (CH₃ CH ₂)₂N); 2,84 (2H, t, CH₂S); 3,04(2H, m, CH₂Ar); 3,47 (2H, t, CH₂N); 4,28 (2H, m, CH₂N_(cycl.));7,09-7,70 (9H, m, ArH).

Calcd for C₂₁H₂₇N₃S: C 71,3; H 7,7; N 11;9. Found: C 71,4; H 7,7; N11;7.

Dihydrochloride of XXI was obtained in 67% yield, m.p. 129-130° C. (fromabs. ethanol with ethylacetate). ¹H NMR (CDCl₃), δ: 1,38 (6H, t, (CH₃CH₂)₂N); 3,26 (2H, t, CH₂Ar); 3,24 (2H, m, CH₂S); 3,35 (4H, q, (CH₃ CH₂)₂N); 3,54 (2H, m, CH₂N); 4,76 (2H, t, CH₂N_(cycl.)); 6,9-7,9 (9H, m,ArH).

Calcd for C₂₁H₂₇N₃S*2HCl: C 59,1; H 6,9; Cl 16,6; N 9,9; S 7,5. Found: C59,1; H 6,8; Cl 16,3; N 10,0; S 7,3.

Example 22. 1-(β-Phenylethyl)-2-[2-morpholino)ethylthio]benzimidazole(XXII) and its dihydrochloride were synthesized as described above. Thereaction of 2,54 g (0,010 mol) 1-(β-phenylethyl)-2-mercaptobenzimidazoleand 2,04 g (0,011 mol) 2-(morpholino)ethylchloride hydrochloride in thepresence of 1 g (0,025 mol) sodium hydroxide gave in 73% yield (2,7 g)compound XXII, m.p. 66-67° C. (from hexane). ¹H NMR (CDCl₃), δ: 2,51(4H,m, CH₂NCH₂ of morpholine); 2,74 (2H, t, CH₂S); 3,04 (2H, m, CH₂Ar);3,51 (2H, t, CH₂N); 3,70 (4H, m, CH₂OCH₂ of morpholine); 4,31 (2H, m,CH₂N_(cycl.)); 7,05-7,70 (9H, m, ArH).

Calcd for C₂₁H₂₅N₃OS: C 68,6; H 6,9; N 11,4; S 8,7. Found: C 68,5; H7,0; N 11,5; S 8,9.

Dihydrochloride of XXII was obtained in 70% yield, m.p. 179-180° C.(from abs. ethanol with ethylacetate). ¹H NMR (D₂O), δ: 3,28 (2H, broadt, CH₂Ar); 3,37 (2H, m, CH₂S); 3,44 (4H, CH₂NCH₂ of morpholine); 3,58(2H, m, CH₂N); 4,08 (4H, m, CH₂OCH₂ of morpholine); 4,76 (2H, broad t,CH₂N_(cycl.)); 6,9-7,9 (9H, m ArH).

Calcd for C₂₁H₂₅N₃OS*2HCl: C 57,3; H 6,2; Cl 16,1; N 9,5; S 7,3. Found:C 57,1; H 5,8; Cl 15,8; N 9,8; S 7,8.

The Industrial Usage The Results of the Pharmacological Study of AppliedCompounds

For revealing an anxiolytic effect of the new compounds the measurementof locomotor activity in the “open-field” test which allows to estimatenot only the expression of anxiolytic effect but also the degree of itsselectivity [Seredenin S. B. et al., Bull.Exp.Biol.Med., 1979, v.88, N7,p.38; Seredenin S. B. et al., in: “Drug Dependence and EmotionalBehavior”, Ed. by Valdman A. V., Consult Bureau, New-York, London, 1987,p.49-77] was used. The main point of this approach consists incomparative analysis of the behavioural effects of tested compounds intwo inbred strains of mice Balb/c and C57B1/6 with different hereditarytypes of emotional-stress reactions (ESR). The anxiolytic effect wasestimated as the activation of the locomotor activity of animals with“passive” type of ESR (Balb/c mice). The main index describing thesedative properties of tested drugs was the inhibition of the locomotoractivity of mice with “active” type of ESR (C57B1/6 strain). Theanxioselectivity was evaluated according to coincidence of doses rangewhich activated or inhibited the behavior of mice of different strains.Earlier this approach has been successfully used for estimation ofanxioselective activity of such known drugs as phenazepam [Seredenin S.B. et al., Bull.Exp.Biol.Med., 1979, v.88, N7, p.38; Seredenin S. B. etal., Ann.Inst.Super.Sanita, 1990, v.26, N1, p.81-88], mexidol [SeredeninS. B. et al., Khimiko-Farmatsevt.Zhurnal, 1987, N2, p.134; Vironina T.A., Seredenin S. B., Ann.Inst.Super.Sanita, 1988, v.24, N3, p.461-466]and gidazepam [Seredenin S. B. et al., in: “Gidazepam” Kiev, NaukovaDumka, 1992, p.92; Seredenin S. B., Blednov Yu. A., Phys.Chem.Biol.Med.,1993, v.1, N1, p.53-60].

Male C57B1/6 and Balb/c mice (“Stolbovaya” animal farm), weighing 20-22g were used. The animals were housed in a separate animal room in groupsof ten and maintained on 12 h light-dark cycle (light from 8.00 till20.00) with free access to standard food and water during two weeksbefore experiment. Testing was performed between 9.00 and 13.00. Everyused compound was administered intraperitoneally in water solutions 30min before testing (0,1 ml solution per 10 g of weight). The“open-field” apparatus consisted of cylinder closed from one end,illuminated by four 75 W lamps fixed to the walls 100 cm above thefloor. The “open-field” apparatus was 100 cm in diameter andwhite-painted; the floor was marked with 3 black circles and some radiallines divided the floor into 16 peripheral and 8 central segments. 30min after injection each animal was placed in the same peripheral squareon the floor for 3 min of testing after 1 min exposure in the darkchamber. The following behavior variables were recorded: 1) the numberof crossings in the peripheral area (peripheral activity); 2) the numberof crossings in the central segments (central activity); 3) the numberof rearings (vertical activity); 4) the emotionality was measured as thenumber of defecations during the test. The sum of all types of locomotoractivity was marked as total activity. The t-Student test was used forstatistical analysis.

The results obtained in screening experiments with usage of geneticmodels allow to divide the tested compounds into 3 groups:

1. The compounds I, VIII, X, XI, XXI and XXII had neither activatory norinhibitory effects on the behavior of mice with “passive” type ofemotional-stress reaction (Balb/c strain) in “open-field” test.

2. On the contrary, the compounds VI (Tab.1), XVI (Tab.2), XVII (Tab.3)and XIX (Tab.4) inhibited the locomotor activity of Balb/c mice in“open-field” test with different degree. These results confirm theabsence of tranquillising-activatory effect of these drugs, but do notexclude the presence of expressed tranquillising-sedative activity(proceeding from low active doses).

3. At last, there were found some compounds: III (Tab.5,6), IV(Tab.7,8), IX (Tab.9,10), XII (Tab.11,12), XIII (Tab.13,14),. XIV(Tab.15,16) and XV (Tab.17,18) which were able to activate the behaviorof Balb/c mice in “open-field” test in wide doses range without anychanges in locomotor activity of animals with “active” type ofemotional-stress reaction (C57B1/6 strain). These data indicate thepresence of expressed selective tranquillising-activatory effect.

The 4 compounds from earlier revealed 3rd group (IV, XII, XIV and XV)demonstrated more expressed anxioselective action at the first stage ofexperiments have been choosen for further more profound study oftranquillising effect and estimation of possible side effects.

The study of anxiolytic activity of chosen compounds was carried out inthe experiments with outbred male rats weighing 180-200 g in standardconflict Vogel' procedure [Voronina T. A. et al., in: “Phenazepam”,Naukova Dumka, Kiev, 1982, p.89, 93, 146]. The main aim of the initialstep of experiments was the training of rats to develop the feeling ofthirst with following experience of water licking from bottle in theexperimental chamber. The animals were deprived of water for 24 hoursand were placed in the test chamber for 5-min adaptation period duringwhich they had free access to the drinking bottle. After another 24 hdeprivation period the rats were placed again in the test chamber andwere allowed to drink water for 5 sec. Immediately afterwards drinkingattempts were punished by electric shock (0,5 mA). Under this collisionof drinking and protective reflexes the extremal situation wasdeveloped. In this situation the anxiety of punishment prevented thelicking process. The number of shocks received throughout a 5-minexperimental session was recorded.

In this test the control animals made from 8 to 14 attempts of punishedlickings (Tab.19). The compounds IV, XII, XIV and XV at doses from 1mg/kg to 20 mg/kg (i.p.) produced the anticonflict (anxiolytic) effect.It was expressed in 2-4 times enhancement of punished licking of waterin comparison with control. Proceeding from results obtained in theseexperiments we can conclude, that the compounds IV, XII, XIV and XVpossessed expressed anxiolytic properties in wide dose range.

The myorelaxant activity of choosen compounds were studied in theoutbred male mice weighing 22-25 g in rotarod test [Voronina T. A. etal., in: “Phenazepam”, Naukova Dumka, Kiev, 1982, p.145]. The animalswere placed on the horizontal rotarod (D=2 cm) calibrated for a fixedspeed of 4 rpm. According to the rotarod experimental protocol, normalmotor coordination was defined by the ability of the animals to remainon the rotarod for an arbitrarily selected time of 120 sec. Datapresented in Tab.20 show that the compound XII at dose range of 0,01mg/kg-50 mg/kg has no effect on the motor coordination. The similarresults were obtained for compounds IV, XIV and XV tested at doses of0,1 mg/kg-20 mg/kg. Thus, the data obtained in this test demonstrate theabsence of myorelaxant activity for any used compound.

The possible hypnotic effects of choosen drugs was estimated accordingto method of potentiation of sleep induced by sodium thiopental. Themale outbred mice weighing 20-25 g were injected i.p. with sodiumthiopental at dose of 70 mg/kg. Two parameters were estimated: latenttime of sleeping and duration of sleep. The used compounds wereadministered i.p. 30 min prior injection of sodium thiopental. Datapresented in Tab.21 demonstrate that every tested drug has no effects onboth the latent time of sleeping and duration of sleep (Tab.22).

The acute toxicity was measured in outbred mice after per osadministration of used drugs in the 1% starch suspension. The lethaldoses were calculated according to Litchfield-Wilcocson' method. TheLD₅₀ value for compound XII was 1,16 g/kg (95% probability: 0,89-1,48g/kg) and was very close to LD₅₀ for another derivative of2-mercaptobenzimidazole known as bimityl. Thus, we can conclude that thecompound XII is not toxic.

The Effects of Choosen Compounds on the Cardiovascular System

The pharmacological studies of salts of applied compounds were carriedout in different models of ischemia and cardiac arrhythmia in comparisonwith the standard drugs such as dihydroxychloride2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole (XXIII),verapamil, propranolol, novocainamide, quinidine, lidocaine, bonnecor.

Anti-ischemic Activity

The effects of compounds on the hemodynamics and activity of intactheart were studied in cats under anesthesia. The experiments werecarried out under conditions of open chest. The phase curve of aorticblood flow was the main index of cardiac activity. The compounds wereadministered i.v. in physiological solution. The t-Student' test wasused to estimate the statistical significance.

It was shown that the compound VIII (1,0 mg/kg), IX (0,5 mg/kg and 1,0mg/kg) and XX (1,0 mg/kg and 2,0 mg/kg) induced the expressedbradycardia which lasted for 30 min after administration. The value ofdouble product which is the indirect index of heart oxygen consumptionalso diminished. It is necessary to take into account that the decreasein heart oxygen consumption is one of the main indexes of antianginaldrugs [Kaverina N. V., Rozonov Y. B., Chichkanov G. G.: The modemaspects of the pharmacology of antianginal drugs, M., Meditsina, 1980,p.240]. The bradycardia induced by used compounds was accompanied by theenhancement of stroke volume. Another parameters of hemodynamics werenot in fact changed (Tab.23,24,25). The prototype-compound XXIII[Saveliev V. L., Moshaeva T. Ya., Chichkanov G. G et al.: Theapplication N 4951704/04 (1991) for patent of Russia, positive decisionon 26.10.1993] also induced the expressed and long bradycardia. However,during 2-3 min after its administration the system blood pressure andmean aortic blood flow acceleration also diminished. This fact indicatesthe inhibition of contractile function of heart (Tab.26). The secondcomparative drug-verapamil also induced the bradycardia and inhibitedthe contractile function of the heart (Tab.27). On the contrary, thecompounds VIII, IX and XX did not inhibited but even slightly enhancedthe contractility of myocardium (the tendency toward the enhancement ofthis parameter appeared).

The compounds VI, X, XII, XVII and XXI at doses of 0,5 mg/kg-2,0 mg/kgproduce a small and short bradycardia and have no effects on the otherparameters of hemodynamics and heart activity.

The compound XV induces the small, but statistically significantbradycardia at a dose of 5 mg/kg.

The compounds XI, XVI, XVIII, XIX and XXII have no effects on theparameters of hemodynamics and heart activity. Basing on these resultsthe compounds VIII, IX and XX have been choosen for further indepthinvestigation.

To demonstrate of protective effect of used drugs on the ischemizedmyocardium it was necessary to carry out the experiments in the model ofacute coronary deficiency. These experiments were conducted in catsweighing 2,5-4,0 kg under anasthesia by i.v. injection of nembutal (40mg/kg) in open chest conditions. Epicardium electrogram in 3-4 leads wasregistered in “Mingograph-81”. The value of mean elevation of ST-segmentduring 5 min occlusions of anterior left descending coronary artery with15 min reperfusions between them was the main index of intensity ofreversible ischemized damage of myocardium. The adequacy of this modelwas earlier verified with propranolol, nitroglycerin and verapamil whichproduced the expressed anti-ischemic action [Tsorin I. B.: Ph.DDissertation, M., 1985, p.148].

The statistical calculation was carried out with non-parametricWilcocson method for associated variants.

There were carried out two series of experiments 6-7 animals in each.The results obtained from these experiments have shown that thecompounds VIII and IX at a dose of 1,0 mg/kg (i.v.) decreased the meanelevation of ST-segment in multiple leads of epicardium electrogramduring 5 min occlusion of coronary artery. But if the compound VIII waseffective immediately after occlusion, the compound IX produced theanti-ischemic effect during 40 min after its injection (Tab.28,29). Theprototype XXIII has a similar effect in this model, but only under itspermanent infusion. After bolus injection its effect was very short(FIG. 1). Verapamil also improves the functional state of ischemic focusin this model but with expressed inhibition of contractility heartfunction [Tsorin I. B.: PhD Thesis, M., 1985, p.148].

Thus, the compounds VIII and IX produced the anti-ischemic action, whichis probably associated with the decrease in heart oxygen consumption asthe result of induced bradycardia. The advantage of tested novelcompounds in comparison with prototypes (compound XXIII and verapamil)is the induction of bradycardia without inhibition (even for a shorttime) of myocardium contractility function.

The presented data allowed to suggest that the compounds VIII and IXbelong to the novel group of antianginal drugs—selective bradycardicagents like Falipamil (structural analogue of verapamil). The widerstudy of activity of the compound IX has been carried out to confirmthis assumption.

The effects of this compound on contractile and pump functions ofischemized myocardium were studied in cats weighing 3,0-4,5 kg underanesthesia with nembutal (40 mg/kg). Under open chest conditions theocclusion of anterior left descending coronary artery was carried outfor 20-40 min and it was changed by 30-50 min reperfusion respectively.The phase curve of blood flow in ascending part of the aortic arch wasrecorded with electromagnetic blood flowmeter MFV-1200 (“Nihon-Kohden”,Japan). Hemodynamics, heart activity values and the number of arrhythmiawere calculated. In the experiments with 40 min ischemia immediatelyafter 60 min the intact and ischemized zones of left ventricle weredissected and freezed in liquid nitrogen. ATP level was measured usinghexokinase method in these zones. 4 series of experiments (2-control and2-basic) were conducted in 12 cats in each. For statistical calculationthe t-Student and Fisher's precision test were used.

The data obtained from these experiments have shown that compound IX(bolus injection at a dose of 1,0 mg/kg immediately after occlusion +50mcg/kg/min i.v. during 30 min) under conditions of 20 min occlusion withfollowing 30 min reperfusion significantly prevents the inhibition ofcontractile function of myocardium induced by ischemic damage. Theaction of compound IX lasted throughout the experiments while the effectof prototype XXIII was observable only during occlusion period and first10 min of reperfusion. The compound IX prevented the decrease in cardiacoutput. But the the cardiac output remained steady to less extent thatis probably due to expressed bradycardia induced by these drugs (FIG.2,3).

It is necessary to stress that in control experiments different types ofarrhythmia appeared very often during occlusion and reperfusion periods.The compound IX decreased the number of arrhythmias which occurred underthese conditions.

Under critical ischemia (40 min occlusion and 60 min reperfusion ofcoronary artery) the compound IX prevented the inhibition of contractilefunction of heart induced by ischemic damage of myocardium. Thiscompound also prevented the decrease in stroke volume and had no effecton changes in cardiac output (FIG. 4). Under conditions of critical andmild ischemia the compound IX did not reduced the number of arrhythmiasinduced by occlusion and reperfusion of coronary vessel.

After 40 min occlusion and 60 min reperfusion of coronary artery inischemized myocardium the ATP level significantly declined (−46,4±5,6%)when compared with intact area. The compound IX increased the ATP levelin the ischemized myocardium and did not change it in the intact zones.At the same time the prototype did not change the ATP level (FIG. 5).

Thus, the compound IX under ischemia of different duration withfollowing reperfusion prevents the inhibition of pump and contractilefunctions of heart. This compound increases the ATP level in theischemized myocardium in comparison with prototype.

It is well known that the classic bradycardic compounds like alinidineand falipamil demonstrate an expressed antiarrhythmic effect. In thisrespect it was interesting to study the effect of compounds IX and XX indifferent models with disturbances of cardiac rhythm.

Antiarrhythmic Activity

Antiarrhythmic properties of applied compounds were studied inadrenaline model in concious rabbits, in calcium chloride and aconitinemodels in concious rats, in the model of ventricular fibrillation inanesthetized rats and in Harris's model in concious dogs.

Adrenaline arrhythmia. The 0,1% solution of adrenaline hydrochloride wasinjected to the marginal ear's vein of rabbit weighing 2,5-3,0 kg atdose ranging 120-150 mcg/kg which induced cardiac rhythm disturbances oftwo types. In one case immediately after injection of very high doses ofadrenaline (150-160 mcg/kg) the polyfocus extrasystoles occurred and waschanged by ventricular tachycardia and fibrillation. In other cases theventricular extrasystole occurred on the background of bradycardia withatrioventricular block of different extent which was transformed topolyfocus extrasystoles and ventricular tachycardia in 2-3 min. In thiscase the bradycardia had a reflex character and developed as response tothe enhancement of blood pressure induced by adrenaline.

The tested compound was injected in 3 ml of distilled water 30 min afterdetermination of arrhythmogenic dose of adrenaline and the ECG wasrecorded in 2nd standard lead. 2 min after administration of testedcompound the arrhythmogenic dose of adrenaline was injected. Theantiarrhythmic efficacy of tested compound was determined according toits ability to prevent the rabbit's death as the result of lethalventricular fibrillation and appearance of arrhythmia. Data presented inTab.30 show that the compounds IX and XX induce the similarantiarrhythmic effect as verapamil and propranolol (antiarrhythmicagents of the 4th and 2nd classes respectively). But the antiarrhythmiceffect of tested compounds was higher when compared with quinidine andlidocaine (antiarrhythmic drugs of the 1st class).

Calcium Chloride Arrhythmia in Rats.

In these experiments the outbred concious rats 180-200 g of weight wereinjected with 10% solution of calcium chloride in tail vein at doserange of 250-300 mg/kg. Usually the ventricular fibrillation occurs 1-2min after injection. But sometimes immediately after injection theexpressed synus bradycardia with ventricular extrasystole transformingto volley of ventricular tachycardia with final ventricular fibrillationdevelop. The injection of tested compounds IX and XX 2 min prior calciumchloride administration prevents the death of animals as the result oflethal venricular fibrillation. The mean effective doses of thecompounds IX and XX were 1,0 mg/kg and 2,03 mg/kg respectively and thisis indicative of their high antiarrhythmic activity. As to the activityof the compound IX it was 50-folds and 7,5-folds higher than that of thenovocainamide and lidocaine respectively.

Aconitine arrhythmia. The aconitine arrhythmia was induced in conciousrats weighing 180-200 g by the injection in tail vein of the aconitinesulfate solution at dose range of 40-50 mg/kg. Mixed atrioventriculardisturbances of rhythm (usually the polyfocus extrasystole) wereobserved. The tested compounds were administered i.v. 3 min prioraconitine injection. The ED₅₀ value was calculated according toLitchfield's method.

The results obtained from the study in this model have shown that thecompound IX produced a high activity: ED₅₀=1,2 mg/kg, LD₅₀=31,5 mg/kg(after i.v. injection), the antiaarhythmic index (LD₅₀/ED₅₀)=26,2(Tab.30). The activity of this compound was higher than that of theknown antiarrhythmic drugs of the 1st class as quinidine and lidocainein 4,4-folds and 6,5-folds respectively. The spectrum of its therapeuticaction was also wider if compared with the standard drugs.

The Study of Antifibrillartory Properties of Compounds IX and XX in Rats

The experiments were conducted in male rats weighing 180-240 g andanesthetized with nembutal (60 mg/kg i.v.) with open chest andartificial respiration. The occlusion of the left coronary artery wasperformed 1-2 min after experiment beginning with following reperfusionafter 7 min. During this period time according to literature data[Krzeminski T., Grzyb J., Kurcok A., Brus R.: Pol.J.Pharmacol., 1992,44, Suppl., p.169-170] the maximum number of ventricular fibrillations(70-100%) were registered. The ECG in the 2nd standard lead was recordedin “Mingograph-81”. The number of ventricular fibrillations duringocclusion and reperfusion periods, the life menacing arrhythmia(fibrillation+paroxysmal ventricular tachycardia) and total number ofarrhythmias were calculated. The known antiarrhythmic drug bonnecor wasused as the reference agent [Grigorieva E. K., Gorbunova V. V. in: “Newantiarrhythmic drug—bonnecor (the pharmacology and clinical usage)”, M.,1993, p.64-67]. The compounds were injected i.v. at the following doses:bonnecor—1,0 mg/kg, compound IX—2,0 mg/kg, compound XX—1,0 mg/kg. Thecontrol animals were administered with the equivalent volume ofphysiological solution (1,0 ml/kg). 4 series of experiments were carriedout in 80 rats. The results were assessed according to the method ofpoint scale: the absence of arrhythmia—0 point, extrasystole—1 point,paroxysmal ventricular tachycardia—2 points, ventricular fibrillation—3points, fibrillation observed during the occlusion of coronary vessel—4points. For statistical analysis the Fisher's exact probability andWilconson's methods were used.

[Krzeminski T., Grzyb J., Kurcok A., Brus R.: Pol.J.Pharmacol., 1992,44, Suppl., p.169-170] have shown that 7 min occlusion with followingreperfusion of coronary artery in anesthetized rats produced theventricular fibrillation (68-100%). Defibrotide and prostacyclinedecreased the number of fibrillations. We have studied theantifibrillator activity of some derivatives of 2-mercaptbenzimidazolein this model with disturbances of heart rhythm. Bonnecor (1,0 mg/kg)was used as the reference drug. It is well known that this agentproduces apronouncedantifibrillatoryactivity [Grigorieva E. K.,Gorbunova V. V. in: “New antiarrhythmic drug-bonnecor (the pharmacologyand clinical usage)”, M., 1993, p.64-67].

The data obtained from the control experiments have shown thatventricular fibrillations were observed in 15 cases out of 24 (62,5%)and lethality hazardous arrhythmia (fibrillation+paroxysmal ventriculartachycardia)—in 22 cases (91,7%). Under these conditions bonnecordecreased the number of both the ventricular fibrillations and lethalityhazardous arrhythmia. Not only the total number but the degree ofarrhythmias expression decreased (according to point scalecalculations).

The compound IX at a dose of 2,0 mg/kg like bonnecor also reduced thenumber of both the ventricular fibrillations and lethality hazardousarrhythmia (Tab.31). The compound X at a dose of 1,0 mg/kg wascharacterised only by a trend to decrease the number of ventricularfibrillations, but it significantly reduced the number of arrhythmiahazardous for life and their manifestation degree (tab.31).

Thus, the tested compounds produced the antifibrillatory effect. Wewould like to note that classic drug with bradycardic type ofaction—alanidine also has the antifibrillatory effect [Uprichard A. C.G., Chi J. J. et al., J.Cardiovas.Pgarmacol., 1989, 14, p.475-482].

The arrhythmia in concious dogs according to Harris. The experimentswere conducted in mongrel dogs of either sex weighing 9-14 kg. Underanesthesia (40 mg/kg of nembutal i.v.) and artificial respiration thetwo-step occlusion of the left anterior descending coronary artery wasperformed. The constant ECG disturbances of the heart rhythm wererecorded after 24 hours. The compounds IX and XX were injected iv. inwater solutions at a dose of 2,0 mg/kg. T-Student' test was used forstatistical calculation.

The results obtained from these experiments have demonstrated that thecompound IX produced the gradual bradycardia. The antiarrhythmic effectof this drug was revealed in every used animal and continued for 50 minin spite of a high basal level of the ectopic activity. The duration ofthe prototype XXIII effect shorter (Tab.32,33). On the background ofcompound IX effect the mild excitation was usually observed. Mostprobably this excitation is the main reason preventing the developmentof the pronounced bradycardia immediately after drug administration.

The compound XX also produced the pronounced bradycardia independentlyon basal level of ectopic activity. This drug also induced theantiarrhythmic effect (Tab.34; FIG. 6). In the experiments with highlevel of ectopia (N1 and N4) the antiarrhythmic effect was weak andpresent only for 10-15 min. In the experiment with mild ectopic activity(N3) the complete block of compound-induced arrhythmia was revealed. Inthis case the tendency to restore the arrhythmia was marked only in30-40 min. In the experiment N2 the antiarrhythmic effect was weak andshort. It is important that even in the experiments when theantiarrhythmic effect was weak (according to percent calculations ofectopic contractions) the compounds XX had the positive action. Itprevented the paroxysms of ventricular tachycardia and extrasystoles andinduced the development of steady rhythm. The compound XX is welltolerated by the animals and possessed some sedative activity.

Thus, the compounds IX and XX produce the the pronounced antiarrhythmiceffect and have no side effects in concious dogs with ventriculardisturbances of heart rhythm.

So, some compounds were revealed among 2-mercaptobenzimidazolederivatives which produce the expressed bradycardia and have no effectson the other parameters of hemodynamics and heart function. This factallows to refer these compounds to the group of specific bradycardicagents. These compounds also possess the expressed anti-ischemic andantiarrhythmic actions.

DESCRIPTIONS OF FIGURES

FIG. 1. The effects of the compound XXIII (1,0 mg/kg+50 mcg/kg/min i.v.)on the mean value of the ST segment elavatation in the epicardiacelectrogramm during 5-min occlusion of coronary artery. Ordinateaxis—mean ST segment elevation in mV; absciss axis—time of the occlusionand the reperfusion of coronary artery in min. 1—control occlusion;2—the occlusion immediately after beginning of compound injection; 3—in20 min. *−P<0,05; {circumflex over ( )}−P<0,1 in comparison with controlocclusion.

FIG. 2. The effects of the compound IX on the pump and contractile heartfunction under conditions of 20-min occlusion and 30-min reperfusion ofthe coronary artery. Ordinate axis—changes in comparison with basallevel in %; absciss axis—time of the occlusion and reperfusion in min.I—stroke volume; II—cardiac volume; III—mean accelaration of blood flowin aorta. -control; ||-compound IX. ú−P<0,1; *−P<0,05; **−P<0,01 incomparison with control.

FIG. 3. The effects of the compound XXIII on the pump and contractileheart function under conditions of 20-min occlusion and 30-minreperfusion of the coronary artery. Ordinate axis—changes in comparisonwith basal level in %; absciss axis—time of the occlusion andreperfusion in min. I—stroke volume; II—cardiac volume; III—meanaccelaration of blood flow in aorta. -control; ||-compound IX. ú−P<0,1;*−P<0,05; **−P<0,01 in comparison with control.

FIG. 4. The effects of the compound IX on the hemodynamics and heartactivity under conditions of 40-min occlusion and 60-min reperfusion ofthe coronary artery. Ordinate axis—changes in the parameters in %;absciss axis—time of the occlusion and reperfusion in min. Thecurve—control; columns—compound IX. {circumflex over ( )}−P<0,1;*−P<0,05; **−P<0,01 in comparison with control.

FIG. 5. The effects of the compound IX on the ATP level in intact andischemized myocardium of the left ventricule of cat after 40-minocllusion and following 60-min reperfusion of the coronary artery.||-intact zone of myocardium from the ischemized left ventricule;-ischemized zone of myocardium. I—control; II—compound IX. Ordinateaxis—the level of ATP in mcM/g of wheight. **−P<0,02 in comparison withintact zone; ++−P<0,02 in comparison with control.

FIG. 6. The effects of the compound XX (1,0 mg/kg i.v.) on the ectopicactivity of heart in concious dogs according to Harris. Left ordinateaxis—the changes in the of frequency of the ectopic contractions in %(curve); Right ordinate axis—the changes in the heart rate in beats/min(columns); absciss axis—time after injection of the compound in min.*−P<0,05 in comparison with basal level of ectopic activity; +−P<0,05 incomparison with basal level of the heart rate.

TABLE 1 The effect of compound VI on the behavior of Balb/cmice in“open-field” test (M ± m_(x)). Types of activity Doses Number of (mg/kg)Peripheral Central Vertical defecations Total Control 8.8 ± 1.6 — — 1.0± 0.7 8.8 ± 1.6 n = 8 0.1 3.0 ± 1.8 — — — 3.0 ± 1.8 n = 8 * * 1.0 3.3 ±1.3 — 0.4 ± 0.4 — 3.7 ± 1.7 n = 9 * * 10.0 3.1 ± 0.8 — — — 3.1 ± 0.8 n =8 ** ** n - number of animals; *. ** N *** - statistically significantfrom correspondent control (P<0.05, P<0.01 and P<0.001 respectively,t-Student test).

TABLE 2 The effect of the compound XVI on the behavior of Balb/c mice in“open-field” test (M ± m_(x)) Types of activity Doses Number of (mg/kg)Peripheral Central Vertical defecation Total Control 17.4 ± 3.2 0.2 ±0.2 — 0.5 ± 0.3 17.6 ± 3.4 n = 16 0.1 3.3 ± 1.1 — — 3.0 ± 0.7 3.3 ± 1.1n = 8 ** *** 1.C 5.3 ± 0.7 — — — 5.3 ± 0.7 n = 8 ** ** 5.0 7.0 ± 2.8 — —0.5 ± 0.5 7.0 ± 2.8 n = 8 * * Look the note in Tab. 1.

TABLE 3 The effect of the compound XVII on the behavior of Balb/c micein “open-field” test (M ± m_(x)) Types of activity Doses Number of(mg/kg) Peripheral Central Vertical defecation Total Control 17.8 ± 3.80.2 ± 0.2 — 0.5 ± 0.1 18.0 ± 4.0 n = 16 0.1 4.0 ± 1.0 0.5 ± 0.5 — 2.0 ±0.8 4.5 ± 1.5 n = 8 ** ** 1.0 7.7 ± 1.9 — — 0.1 ± 0.1 7.7 ± i.9 n =8 * * Look the note in Tab. 1.

TABLE 4 The effect of the compound XIX on the behavior of Balb/c mice in“open field” test (M ± m_(x)). Types of activity Doses Numbers of(mg/kg) Peripheral Central Vertical defecation Total Control 8.8 ± 1.6 —— 1.0 ± 0.7 8.8 ± 1.6 n = 8 0.1 2.7 ± 1.0 0.3 ± 0.3 — 0.4 ± 0.4 3.0 ±1.3 n = 8 ** ** 1.0 3.1 ± 0.9 0.4 ± 0.4 0.1 ± 0.1 0.9 ± 0.6 3.6 ± 1.4 n= 8 ** ** 10.0 1.8 ± 0.5 — — 0.5 ± 0.5 1.8 ± 0.5 n = 8 *** *** Look thenote in Tab. 1

TABLE 5 The effect of the compound III on the behavior of Balb/c in“open-field” test (M ± m_(x)) Types of activity Doses Numbers of (mg/kg)Peripheral Central Vertical defecation Total Control 16.8 ± 2.7 1.8 ±1.7 — 2.0 ± 0.8 18.8 ± 6.8 n = 8 0.1 28.1 ± 5.8 3.3 ± 2.0 0.6 ± 0.4 2.5± 0.9 32.1 ± 7.9 n = 8 1.0 35.8 ± 6.1 0.6 ± 0.3 — 2.5 ± 0.7 36.4 ± 6.4 n= 8 5.0 46.8 ± 9.9 0.3 ± 0.3 0.4 ± 0.3 3.0 ± 0.7 47.5 ± 10.3 n = 8 * *10.0 56.1 ± 12.2 3.3 ± 2.1 — 2.0 ± 0.7 59.4 ± 13.8 n = 8 * * 20.0 24.0 ±11.5 — — 1.5 ± 0.7 24.1 ± 11.5 n = 8 Look. the note in Tab. 1

TABLE 6 The effect of the compound III on the behavior of C57B1/6 micein “open-field” test (M ± m_(x)). Doses Types of activity (mg/kg)Peripheral Central Vertical Total Control 109.8 ± 10.0 29.6 ± 6.4 21.9 ±2.8 161.8 ± 11.3 n = 8 0.1 109.4 ± 8.3 42.1 ± 4.8 19.4 ± 3.4 170.9 ±10.0 n = 8 0.5 118.4 ± 9.0 42.1 ± 7.5 22.6 ± 2.0 184.6 ± 8.6 n = 8 1.0107.8 ± 7.4 35.9 ± 7.6 22.3 ± 3.8 165.9 ± 13.5 n = 8 5.0 130.8 ± 16.828.8 ± 6.9 18.6 ± 2.7 177.8 ± 20.7 n = 8 10.0 118.0 ± 7.9 23.6 ± 5.312.9 ± 1.8 154.4 ± 13.3 n = 8 50.0 105.2 ± 11.9 24.0 ± 2.7 12.1 ± 1.3141.3 ± 11.7 n = 8 Look the note in Tab. 1

TABLE 7 The effect of the compound IV on the behavior of Balb/c mice in“open-field” test (M ± m_(x)) Types of activity Doses Numbers of (mg/kg)Pepipheral Central Vertical defecation Total Control 5.5 ± 0.8 — — 1.5 ±0.7 5.5 ± 0.8 n = 8 0.1 12.6 ± 2.6 — — 0.6 ± 0.5 12.6 ± 2.6 n = 7 * *1.0 11.4 ± 2.3 — — — 11.4 ± 2.3 n = 7 * * 5.0 13.6 ± 3.5 — — 1.7 ± 0.813.6 ± 3.5 n = 7 * * 10.0 9.5 ± 1.9 — — 3.0 ± 0.7 9.5 ± 1.9 n = 8 * *20.0 8.9 ± 2.0 — — 2.5 ± 0.7 8.9 ± 2.0 n = 8 Look the note in Tab. 1

TABLE 8 The effect of the compound IV on the behavior of C57B1/6 mice in“open-field” test (M ± m_(x)) Types of activity Doses Number of (mg/kg)Peripheral Central Vertical defecation Total Control 64.1 ± 7.1 18.9 ±2.9 10.8 ± 1.5 0.4 ± 0.2 93.8 ± 11.5 n = 8 1.0 62.8 ± 10.6 26.8 ± 4.99.3 ± 1.6 0.4 ± 0.2 99.3 ± 17.1 n = 8 10.0 52.8 ± 11.3 19.3 ± 4.5 11.1 ±3.7 0.1 ± 0.1 83.2 ± 19.5 n = 8 Look the note in Tab. 1

TABLE 9 The effect of the compound IX on the behavior of Balb/c mice in“open-field” test (M ± m_(x)) Types of activity Doses Numbers of (mg/kg)Peripheral Central Vertical defecation Total Control 19.4 ± 4.1 — — 0.6± 0.6 19.9 ± 4.1 n = 18 0.1 15.1 ± 9.0 — — 0.1 ± 0.1 15.1 ± 9.0 n = 81.0 39.8 ± 7.3 — — — 39.8 ± 7.3 n = 8 * * 5.0 44.1 ± 10.2 — — — 44.1 ±10.2 n = 8 * * 10.0 36.8 ± 5.0 — — — 36.8 ± 5.0 n = 8 * * 20.0 17.8 ±5.5 — — — 17.8 ± 5.5 n = 8 Look the note in Tab. 1

TABLE 10 The effect of the compound IX on the behavior of C57B1/6 micein “open-field” test (M ± m_(x)) Types of activity Doses Numbers of(mg/kg) Peripheral Central Vertical defecation Total Control 86.3 ± 10.741.6 ± 10.0 11.4 ± 2.9 2.0 ± 0.8 139.3 ± 19.6 n = 8 1.0 70.9 ± 26.0 26.5± 4.3 8.1 ± 1.6 1.0 ± 0.7 106.8 ± 6.6 n = 8 5.0 78.8 ± 14.5 34.3 ± 12.910.8 ± 3.2 0.5 ± 0.5 125.0 ± 21.9 n = 8 10.0 70.6 ± 10.8 24.6 ± 8.2 11.3± 2.9 1.0 ± 0.7 106.6 ± 18.5 n = 8 Look the note in Tab. 1

TABLE 11 The effect of the compound XII on the behavior of Balb/c in“open-field” test (M ± m_(x)) Types of activity Doses Numbers of (mg/kg)Peripheral Central Vertical defecation Total Control 20.6 ± 1.9 0.3 ±0.2 0.1 ± 0.1 1.5 ± 0.3 21.0 ± 2.2 n = 42 0.001 28.9 ± 8.8 1.6 ± 1.6 — —30.3 ± 9.4 n = 10 0.01 79.8 ± 9.3 2.6 ± 1.4 0.9 ± 0.6 3.1 ± 0.6 83.2 ±11.3 n = 9 *** * *** 0.05 37.1 ± 6.7 — — 2.0 ± 0.8 37.1 ± 6.7 n = 8 * *0.1 70.6 ± 10.6 3.1 ± 2..1 — 2.4 ± 0.7 73.7 ± 12.7 n = 10 *** * *** 0.577.6 ± 14.2 2.9 ± 1.5 — 1.6 ± 0.8 80.5 ± 15.7 n = 10 *** ** 1.0 66.3 ±11.1 0.5 ± 0.3 — 2.8 ± 0.9 66.8 ± 11.4 n = 10 *** *** 5.0 43.0 ± 4.4 2.3± 1.5 — 0.8 ± 0.5 45.3 ± 5.9 n = 10 *** * 10.0 54.8 ± 8.3 0.9 ± 0.3 —2.0 ± 0.7 55.7 ± 8.6 n = 10 *** *** 30.0 50.5 ± 7.9 1.1 ± 0.7 0.1 ± 0.14.5 ± 1.4 51.7 ± 8.7 n = 8 *** *** 50.0 11.0 ± 1.6 — — 1.6 ± 0.5 11.0 ±1.6 n = 14 *** *** Look the note in Tab. 1

TABLE 12 The effect of the compound XII on the behavior of C57B1/6 in“open-field” test (M ± m_(x)). Types of activities Doses Numbers of(mg/kg) Pepiferal Central Vertical defecations Total Control 85.1 ± 4.323.6 ± 4.8 18.8 ± 2.6 2.0 ± 0.8 127.5 ± 11.7 n = 17 0.1 92.9 ± 5.4 18.3± 1.9 12.5 ± 1.1 1.3 ± 0.3 123.6 ± 8.4 n = 8 1.0 86.6 ± 4.3 20.4 ± 2.316.5 ± 1.8 0.5 ± 0.5 123.5 ± 8.4 n = 8 10.0 86.6 ± 10.9 36.0 ± 4.9 17.6± 3.2 0.6 ± 0.6 140.2 ± 19.0 n = 8 20.0 86.4 ± 4.0 23.4 ± 4.9 17.4 ± 2.71.8 ± 0.6 127.2 ± 11.6 n = 8 30.0 53.0 ± 5.7 26.3 ± 10.2 8.3 ± 4.6 0.1 ±0.1 87.9 ± 17.5 n = 8 *** ** * * 50.0 67.1 ± 11.9 13.9 ± 5.3 9.1 ± 2.60.5 ± 0.3 90.1 ± 19.8 n = 8 * Look the note to Tab. 1

TABLE 13 The effect of the compound XIII on the behavior of Balb/c micein “open-field” test (M ± m_(x)) Types of activity Doses Numbers of(mg/kg) Pepipheral Central Vertical defecation Total Control 20.8 ± 5.22.1 ± 1.6 — 1.6 ± 1.0 22.9 ± 6.8 n = 10 0.5 32.0 ± 5.7 4.3 ± 4.1 — 2.9 ±0.6 36.3 ± 9.8 n = 10 1.0 80.0 ± 11.2 0.8 ± 0.5 — 1.0 ± 0.5 80.8 ± 11.7n = 10 ** ** 5.0 69.0 ± 13.2 — — 1.6 ± 0.7 69.0 ± 13.2 n = 10 ** ** 50.027.7 ± 6.2 0.7 ± 0.5 — — 28.4 ± 6.7 n = 10 Look the note in Tab. 1

TABLE 14 The effect of the compound XIII on the behavior of C57B1/6 in“open-field” test (M ± m_(x)) Doses Types of activity (mg/kg) PeripheralCentral Vertical Total Control 79.8 ± 9.9 33.3 ± 6.3 16.3 ± 2.6 129.4 ±18.8 n = 8 1.0 79.6 ± 5.3 37.6 ± 7.9 14.8 ± 2.7 132.0 ± 15.9 n = 8 10.084.1 ± 9.9 22.4 ± 3.5 12.9 ± 3.5 119.4 ± 16.4 n = 8 50.0 63.3 ± 8.4 20.0± 5.3 11.8 ± 3.0 95.1 ± 16.7 n = 8 Look the note in Tab. 1

TABLE 15 The effect of the compound XIV on the behavior of Balb/c micein “open field” test (M ± m_(x)) Types of activity Doses Numbers of(mg/kg) Peripheral Central Vertical defecation Total Control 20.0 ± 2.70.7 ± 0.4 0.2 ± 0.1 1.5 ± 0.3 20.9 ± 3.2 n = 23 0.1 27.0 ± 6.3 1.1 ± 0.70.1 ± 0.1 1.3 ± 0.5 28.2 ± 7.1 n = 14 * 0.5 44.4 ± 9.2 4.7 ± 2.7 0.3 ±0.3 1.0 ± 0.4 49.4 ± 10.7 n = 14 * * 1.0 38.7 ± 4.8 0.9 ± 0.8 0.1 ± 0.12.9 ± 0.7 39.7 ± 5.7 n = 14 ** ** 5.0 58.7 ± 7.2 2.8 ± 1.8 — 0.7 ± 0.761.3 ± 9.0 n = 6 *** *** 10.0 67.8 ± 11.1 — — 2.0 ± 0.9 67.8 ± 11.1 n =6 *** *** 20.0 17.3 ± 8.0 3.4 ± 3.4 0.1 ± 0.1 0.1 ± 0.1 20.8 ± 9.6 n = 8Look the note in Tab. 1

TABLE 16 The effect of the compound XIV on the behavior of C57B1/6 in“open-field” test (M ± m_(x)) Doses Types of activity (mg/kg) PeripheralCentral Vertical Total Control 72.1 ± 9.0 30.5 ± 7.2 13.5 ± 2.3 116.1 ±18.5 n = 8 0.5 78.4 ± 9.8 24.8 ± 4.6 11.0 ± 2.9 114.2 ± 17.3 n = 8 5.069.5 ± 11.3 37.1 ± 4.7 12.5 ± 2.1 119.1 ± 18.1 n = 8 10.0 79.0 ± 6.835.1 ± 5.0 15.3 ± 3.2 129.4 ± 15.0 n = 8 Look the note in Tab. 1

TABLE 17 The effect of the compound XV on the behavior of Balb/c in“open-field” test (M ± m_(x)). Types of activity Doses Numbers of(mg/kg) Periphepal Central Vertical defecation Total Control 17.6 ± 2.71.9 ± 1.5 — 1.8 ± 0.9 19.5 ± 4.2 n = 11 0.5 32.1 ± 4.7 0.5 ± 0.4 — 1.6 ±0.7 32.6 ± 5.0 n = 10 * * 1.0 37.7 ± 5.5 5.1 ± 4.4 — 2.0 ± 0.9 42.8 ±9.9 n = 10 ** 5.0 39.1 ± 8.6 — — 3.6 ± 0.9 39.1 ± 8.6 n = 10 * * 75.08.8 ± 2.9 — — 2.7 ± 1.3 8.8 ± 2.9 n = 6 * * 100.0 6.5 ± 3.1 — — — 6.5 ±3.1 n = 6 * * Control 13.8 ± 5.4 — — 2.0 ± 0.8 13.8 ± 5.4 n = 8 0.01 6.9± 1.8 — — 0.5 ± 0.5 6.9 ± 1.8 n = 8 0.1 11.1 ± 2.1 — — 1.0 ± 0.7 11.2 ±2.1 n = 8 10.0 44.9 ± 13.0 0.6 ± 0.5 0.4 ± 0.3 — — 45.9 ± 13.8 n = 8 * *Look the note in Tab. 1

TABLE 18 The effect of the compound XV on the behavior of C57B1/6 micein “open-field” test (M ± m_(x)) Doses Types of activity (mg/kg)Pepipheral Central Vertical Total Control 69.9 ± 4.5 33.6 ± 6.2 12.3 ±0.9 415.8 ± 11.6 n = 8 1.0 87.8 ± 6.7 39.0 ± 6.9 11.4 ± 2.5 138.2 ± 16.1n = 8 5.0 87.8 ± 14.6 36.4 ± 5.7 14.9 ± 2.3 139.1 ± 22.6 n = 8 50.0 54.1± 10.7 35.0 ± 8.1 6.3 ± 1.6 95.4 ± 20.4 n = 8 Look the note in Tab. 1

TABLE 19 The effect of the compounds IV, XII, XIV N XV on the thebehavior of rats in conflict Vogel test (M ± m_(x)). Doses Compounds(mg/kg) XII IV XV XIV Control 8.3 ± 1.5 14.5 ± 3.0 14.5 ± 3.0 14.5 ± 3.0n = 12 n = 13 n = 13 n = 13 1.0 15.3 ± 3.4 29.7 ± 5.3 59.1 ± 16.7 31.6 ±7.6 n = 8 n = 6 n = 8 n = 8 * * * * 5.0 19.0 ± 2.5 31.0 ± 5.6 35.3 ± 5.532.9 ± 5.8 n = 11 n = 6 n = 8 n = 10 ** * ** * 10.0 15.4 ± 2.5 35.8 ±7.8 38.0 ± 9.4 36.0 ± 9.4 n = 11 n = 6 fl = 5 n = 10 * * * * 20.0 28.0 ±5.8 62.3 ± 19.5 73.9 ± 24.1 42.3 ± 10.8 n = 12 n = 6 n = 10 n = 12** * * * Look the note in Tab. 1

TABLE 20 The effects of the compounds IV, XII, XIV N XV on the time ofremaining on the rotarod (sec) (M ± m_(x)) Doses Compounds (mg/kg) XIIIV XV XIV Control 120.0 + 0 120 + 0 120 + 0 120 + 0 n = 16 n = 8 n = 8 n= 8 0.01 120.0 + 0 — — — n = 12 0.1 120.0 + 0 120 + 0 120 + 0 120 + 0 n= 12 n = 8 n = 8 n = 8 1.0 120.0 + 0 120 + 0 120 + 0 120 + 0 n = 12 n =8 n = 8 n = 8 5.0 120.0 + 0 120 + 0 120 + 0 120 + 0 n = 12 n = 8 n = 8 n= 8 10.0 120.0 + 0 120 + 0 120 + 0 120 + 0 n = 12 n = 8 n = 8 n = 8 20.0118.8 + 1.6 120 + 0 120 + 0 120 + 0 n = 12 n = 8 n = 8 n = 8 50.0111.3 + 7.5 — — — n = 12 Look the note in Tab. 1

TABLE 21 The effect of the compounds IV, XII, XIV N XV on the latenttime of sleep (sec) in mice after administration of sodium thiopental (M± m_(x)) Doses Compounds (mg/kg) XII IV XV XIV Control 1.89 + 0.19 2.4 +0.2 2.6 + 0.3 2.6 + 0.4 n = 18 n = 8 n = 8 n = 8 0.01 1.86 + 0.27 — — —n = 8 0.1 1.94 + 0.18 — — — n = 8 0.5 — 3.0 + 0.3 2.5 + 0.2 2.5 + 0.5 n= 8 n = 8 n = 8 1.0 2.78 + 0.17 2.7 + 0.3 2.8 + 0.2 2.5 + 0.2 n = 9 n =8 n = 8 n = 8 5.0 2.21 + 0.17 2.8 + 0.3 2.3 + 0.2 2.2 + 0.2 n = 9 n = 8n = 8 n = 7 10.0 2.28 + 0.24 2.5 + 0.1 2.8 + 0.3 2.9 + 0.4 n = 9 n = 8 n= 8 n = 6 Look the note in Tab. 1

TABLE 22 The effect of the compounds IV, XII, XIV N XV on the durationof sleep (min) in mice after administration of sodium thiopental (M ±m_(x)) Doses Compounds (mg/kg) XII IV XV XIV Control 102.9 ± 14.9 67.7 ±15.7 76.0 ± 14.6 119.5 ± 17.4 n = 18 n = 8 n = 8 n = 8 0.01 76.4 ± 16.7— — — n = 8 0.1 54.5 ± 9.9 — — — n = 8 * 0.5 — 42.8 ± 13.5 78.4 ± 18.291.0 ± 17.8 n = 8 n = 8 n = 8 1.0 67.9 ± 4.3 32.5 ± 7.9 70.5 ± 13.7 69.S± 15.8 n = 9 n = 8 n = 8 n = 8 * * 5.0 71.7 ± 14.6 50.7 ± 11.0 56.8 ±19.1 86.4 ± 13.9 n = 9 n = 8 n = 8 n = 7 10.0 92.4 ± 9.9 45.1 ± 10.674.7 ± 18.7 70.6 ± 9.0 n = 9 n = 8 n = 8 n = 6 * Look the note in Tab. 1

TABLE 23 The effect of the compound VIII at dose of 1.0 mg/kg (i.v.) onthe hemodynamics and intact heart activity in cats (n = 5. M ± m ) Thechanges after drug injection, % from basal level after after after afterafter after Parameter injection 2 min 5 min 10 min 20 min 30 min Meanblood pressure −14.8 ± 12.5 −1.8 ± 3.8 −2.8 ± 5.7 −7.8 ± 5.7 −12.0 ± 5.0−6.5 ± 5.7 Heart rate −15.3 ± 1.1** −10.9 ± 2.3* −3.2 ± 1.4 −4.4 ± 1.9−3.2 ± 1.8 −5.4 ± 3.1 Stroke volume 63.2 ± 14.0* +20.6 ± 6.5* +5.6 ±10.8 −3.5 ± 8.7 −4.5 ± 8.4 +3.5 ± 3.5 Cardiac volume 38.1 ± 11.6* +7.0 ±2.9 +6.0 ± 12.8 −7.5 ± 9.6 −7.2 ± 9.2 −2.2 ± 3.0 Aortic blood flow +31.3± 10.8 +3.3 ± 2.7 −2.0 ± 9.0 −5.2 ± 7.8 −6.2 ± 7.6 +1.2 ± 2.1accelaration * - p < 0.05 ** - p < 0.01 in comparison to basal level

TABLE 24 The effect of the compound IX on the hemodynainics and intactheart activity in cats (n = 7, M ± m) The changes after drug injection,% from basal level Dose after after after after after after Parametermg/kg injection 2 min 5 min 10 min 20 min 30 min Mean blood 0.5 −2.1 ±3.0 +4.4 ± 4.7 −5.4 ± 2.3 −1.2 ± 3.6 −4.1 ± 4.8 −4.9 ± 6.5 pressure 1.0−1.6 ± 7.3 +0.6 ± 2.7 −3.8 ± 3.4 −6.8 ± 2.5* −1.9 ± 2.9 −2.7 ± 2.9 Heartrate 0.5 −8.0 ± 3.5 −11.6 ± 2.8** −91 ± 2.5* −7.3 ± 1.6** −4.5 ± 2.2−5.3 ± 2.3 1.0 −15.4 ± 2.7** −14.1 ± 2.1** −10.6 ± 1.5** −7.1 ± 1.0**−4.2 ± 1.9 −2.3 ± 3.5 Stroke 0.5 +17.0 ± 5.5* +9.4 ± 6.5 +5.6 ± 5.6 +3.6± 3.0 −0.7 ± 4.0 +1.8 ± 9.3 volume 1.0 +34.21 ± 0.6* +19.3 ± 4.6** +13.8± 7.8 +5.9 ± 6.3 +4.4 ± 4.5 +0.7 ± 6.7 Cardiac 0.5 +6.5 ± 2.8 −3.5 ± 6.0−1.7 ± 4.8 −4.2± 2.1 −6.1 ± 3.4 −2.8 ± 7.8 volume 1.0 +17.6 ± 8.2 +2.2 ±3.5 +1.7 ± 6.8 −1.3 ± 6.8 −0.2 ± 3.8 −2.5 ± 5.1 Mean blood 0.5 +8.8 ±5.8 +11.0 ± 8.8 +0.6 ± 4.9 +3.0 ± 4.0 +5.6 ± 5.1 +1.8 ± 5.8 flow 1.0+14.8 ± 8.8 ± 8.6 +3.8 +13.6 ± 5.7 +9.6 ± 3.9* +13.1 ± 5.0* +3.9 ± 2.0accelaration * - p < 0.05 ** - p < 0.01 in comparison to basal level

TABLE 25 The effect of the compound XX on the hemodynamics and intactheart activity in cats (n = 5, M ± m) The changes after drug injection,% from basal level Dose after after after after after after Parametermg/kg injection 2 min 5 min 10 min 20 min 30 min Mean blood 1.0 −0.9 ±2.7 ± 5.1 ± 1.7* +2.0 ± 1.0 +1.7 ± 1.2 +3.3 ± 2.4 +0.3 ± 3.0 pressure2.0 −13.6 ± 5.1 ± 4.6 ± 3.5 +3.3 ± 2.5 −1.0 ± 1.8 −5.3 ± 0.8** −9.6 ±3.5 Heart rate 1.0 −7.9 ± 1.7** −4.9 ± 1.5* −5.2 ± 2.1 −4.3 ± 1.9 −5.0 ±4.2 −5.0 ± 4.2 2.0 −10.7 ± 2.5* −5.2 ± 1.8* −4.5 ± 1.4* −3.1 ± 1.6 −3.6± 1.7 −4.0 ± 2.2 Stroke 1.0 +25.2 ± 2.6** +7.9 ± 1.6** +1.7 ± 3.4 +0.6 ±3.5 +1.4 ± 3.8 −0.5 ± 4.4 volume 2.0 +38.5 ± 10.6* +6.9 ± 3.1 +4.2 ± 3.8+1.8 ± 2.1 −1.1 ± 5.4 +1.7 ± 3.9 Cardiac 1.0 +15.1 ± l.6** +2.5 ± 0.9−3.9 ± 1.5 −3.9 ± 2.8 −4.1 ± 2.8 −7.0 ± 3.4 volume 2.0 +22.7 ± 6.6* +1.2± 2.8 −0.5 ± 3.1 −1.4 ± 3.0 −4.7 ± 5.2 −5.5 ± 5.2 Mean blood 1.0 +10.7 ±3.3* −1.4 +1.8 −3.6 ± 2.4 −0.6 ± 2.1 −2.8 ± 2.6 −3.2 ± 1.8 flow 2.0+22.5 ± 9.3 −3.0 ± 3.9 +1.6 ± 5.1 −1.0 ± 3.1 −3.8 ± 4.0 −6.2 ± 4.9accelaration * - p < 0.05 ** - p < 0.01 in comparison to basal level

TABLE 26 The effect of the compound XXIII (1.0 mg/kg, i.v.) on thehemodynamycs and heart activity. The changes in comparison to basallevel, in %. M ± m, n = 7 Time after injection, min Parameter 0.25 2 510 20 30 Mean blood −13.9 ± 2.9** −0.2 ± 4.0 +3.4 ± 2.5 +3.8 ± 3.2 +2.8± 2.8 +2.9 ± 3.2 pressure Heart rate −14.6 ± 1.2** −11.7 ± 1.3** −7.9 ±1.6** −5.1 ± 1.2** −3.8 ± 1.5* −4.1 ± 1.0* Cardiac +3.6 ± 3.5 −3.6 ± 2.0−0.6 ± 2.3 −0.7 ± 3.6 −4.2 ± 2.4 −4.5 ± 3.5 volume Mean blood +2.1 ± 4.9−4.9 ± 4.7 −1.0 ± 5.0 +8.1 ± 3.0* +4.3 ± 2.7 −2.4 ± 3.4 flowaccelaration * p<0.05 ** p<0.01 in comparison to basal level

TABLE 27 The effect of the verapamil (0.5 mg/kg, i.v.) on thehemodynamics and heart activity The changes in comparison to basallevel, in %, M ± m, n = 7 Time after injection, min Parameter 0.25 2 510 20 30 Mean blood −40.4 ± 7.0** −22.7 ± 8.1 −8.7 ± 6.3 −2.4 ± 2.6 −8.5± 6.6 −11.6 ± 7.0 pressure Heart rate −13.7 ± 1.7** −11.8 ± 2.0** −12.3± 3.0** −8.1 ± 2.0** −5.4 ± 2.0* −4.6 ± 3.4 Cardiac −12.3 ± 4.5* +7.5 ±6.8 +4.4 ± 4.7 −0.3 ± 1.8 −9.5 ± 2.3** −7.2 ± 6.0 volume Mean blood−32.5 ± 5.7** −15.5 ± 2.4** −8.1 ± 3.0* −9.9 ± 2.5** −8.7 ± 3.0 −7.0 ±4.2 flow accelaration * p<0.05 ** p<0.01 in comparison to basal level

TABLE 28 The effect of the compound VIII (1.0 mg/kg, i.v.) on the meanelevation of ST-segment in epicardium electrogram during 5-min occlusionwith following reperfusion of coronary artery in anesthized cats (n = 6)The changes in the elevation of ST-segment in comparison to controlocclusion (probability interval, mv) 30 sec of 1 min of 2 min of 4 minof 5 min of 15 sec of occlusion occlusion occlusion occlusion occlusionreperfusionl Occlusion immediately −1.20* −0.90* −1.25* −0.70 −0.80−0.40 after injection −1.80−−0.50 −1.60−−0.40 −3.00−−0.30 −1.40−±0.30−1.40−0 −0.70−−0.10 Occlusion 20 min −0.45 −0.30 −0.50 −0.50 −0.25 afterinjection −1.00−+0.05 −1.10−+0.60 −2.05−+0.20 −1.00−+0.50 −0.80−+1.0−0.80−+0.20 Occlusion 40 min −0.55 −0.35 −0.40 −0.50 −0.85 −0.75 afterinjection −1.20−+0.1 −1.35−+0.65 −2.00−+0.60 −1.45−+0.70 −1.90−+0.50−1.15−0 * - p < 0.05 in comparison to control occlusion

TABLE 29 The effect of the compound IX (1.0 mg/kg. i.v.) on the meanelevation of ST-segment in epicardium electrogram during 5-min occlusionwith following reperfusion of coronary artery in anethetized cats (n =6) The changes in the elevation of ST-segment in comparison to controlocclusion (probability interval, my) 30 sec of 1 min of 2 min of 3 minof 5 min of 15 sec of occlusion occlusion occlusion occlusion occlusionreperfusion Occlusion immediately −1.8** −1.9** −2.4** −1.9** −2.2**−1.2* after injection −3.1÷−1.4 −2.9÷−0.8 −3.7÷−1.0 −5.8÷−1.0 −6.5÷−0.4−2.3÷−0.2 Occlusion 20 min −0.7 −.0.7 −1.4* −1.4* −1.2 −0.8* afterinjection −2.0÷ 0.0 −1.0÷+0.1 −2.7÷−0.5 −2.7÷−0.2 −3.0÷±0.6 −1.5÷−0.1Occlusion 40 min −0.5 −0.5* −1.0* −1.2 −1.0 −1.0* after injection −1.1 ÷0.0 −1.65÷−0.1 −2.4÷−0.2 −3.8÷+ 0.6 −3.0÷+ 1.0 −1.9÷−0.2 * - p < 0.05** - p < 0.01 in comparison to control level

TABLE 30 The anti-arrhythmic activity of the compounds IX and XXAdrenaline Calcium arrhythmia. chloride Aconitine Acute Range ofarrhythmia arrhythmia toxicity active doses ED50, ED50, LD50, Compoundsmg/kg mg/kg mg/kg mg/kg LD50/ED50 Compound XX 0.2−0.7 2.0 <0.5 no datano data 1.7-2.4 Compound IX 0.3-0.7 1.0 1.2 31.5 26.2 0.7-1.3 0.9-1.531.4-31.6 Novocainamide — 50.0 41 110.0 2.7 Lidocaine 5.0-8.0 7.5 7.839.4 5.0 Bonnecor 1.6 0.23 11.5 50 Etmosin 0.28 16.4 58.6 Verapamil0.3-1.0 1.1 — 17.0 Propranolol 0.3-1.0 0.8 — 9.6

TABLE 31 The effect of the compounds IX, XX and bonnecor on theincidence of ventricular fibrillations and lethality hazardousarrhythmia during 7-min occlusion with following reperfusion of coronaryartery. Number Total of numbers Severity of ani- Number Number ofarrhythmias Compound mals of VF of LHA arrhyt. (in points) Control 2415  22  24  66  Bonnecor 18  6* 12* 16  36* 1, 0 mg/kg Compound 20  4*12*  17{circumflex over ( )}  32** IX 2 mg/kg Compound 18  7{circumflexover ( )} 11*  13** 34* XX 1 mg/kg {circumflex over ( )}p ≦ 0, 1; *p ≦0, 05; **p ≦ 0, 01—in comparison to control VF-ventricular fibrillationsLHA-lethality hazardous arrhythmia (VF + paroxysmal ventriculartachycardia)

TABLE 32 The effect of the compound IX at dose of 2 mg/kg (i.v.) on theventricular disterbances of heart rhythm in concious dogs (n = 5, M ± m). The changes in comparison to basal level after compound injectionafter after after after after after Parameter 3 min 5 min 10 min 20 min30 min 60 min Heart, rate +3.2 ± 8.4 −5.2 ± 9.2 −14.6 ± 12.0 −16.4 ± 6.6& −5.6 ± 2.1 & −5.2 ± 4.1 & beats/min % ectopic −44.8 ± 15.0* −43.8 ±13.3* −59.4 ± 7.8** −41.4 ± 8.1** −24.8 ± 5.8* −17.2 ± 9.1 contractions*p < 0.05 **p < 0.01 in comparison to basal level & - p < 0.1

TABLE 33 The effect of the compound XXIII at dose of 2 mg/kg (i.v.) onthe ventricular disterbances of heart rhythm in concious dogs (n = 5, M± m ). The changes in comparison to basal level after compound injectionafter after after after after after after Parameter 1 min 3 min 5 min 10min 15 min 30 min 60 min Heart rate −19.0 ± 2.5** −25,8 ± 455** −30.4 ±4.5** −32.6 ± 359** −29.0 ± 5.5** −14.0 ± 4.8* −12.0 ± 5.5* beats/min %ectopic −57.4 ± 17.6* −66.2 ± 18.1* −54.6 ± 16.8* −22.6 ± 8.9* −24.8 ±11.1* −8.8 ± 4.7 −5.2 ± 2.6 contractions *p < 0.05 **p < 0.01 incompapison to basal level

TABLE 34 The effect of the compound XX (1.0 mg/kg. i.v.) on the heartrate (beats/min) and % of the ectopic contractions* in concious dogsaccording to Harris. Number of basal Time after compound injection, mindog level 3 5 10 15 20 30 40 50 1 131/97 103/80 98/82 75/81 100/91 78/92117/91 106/97 109/94 2 122/57 93/64 89/52 102/50 88/51 74/56 94/62105/66 128/63 3 183/36 172/30 167/20 163/18 159/0 155/0 168/10 185/8198/10 4 164/88 145/72 138/63 129/60 125/58 132/66 135/74 148/79 159/81*heart rate / % of the ectopic contpactions

What is claimed is:
 1. A compound of the formula

wherein n is 2, R is hydrogen, R¹ is selected from the group consistingof dimethylamino, diethylamino, piperidino, pyrrolidino, morpholino and4-methylpiperazino, R₂ is ethoxy, and R₃ is hydrogen, or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein n=2, R₁=NMe₂, R₂=OEt, and R₃=H.
 3. A compound accordingto claim 1 wherein n=2, R₁=NEt₂, R₂=OEt, and R₃=H.
 4. A compoundaccording to claim 1 wherein n=2, R₁=

R₂=OEt, and R₃=H.